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Inhibiting Mutations in the Transforming Growth Factor ß Type 2 Receptor in Recurrent Human Breast Cancer

Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW [C. D. L., J. C. M., P. R. K., R. H.]; Department of Surgery, Ninewells Hospital and Medical School, Dundee DD1 9SY [A. M. T.]; Department of Oncology, University of Cambridge Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY [A. P.]; and Department of Oncology, Oncology Centre, Addenbrooke’s Hospital, Cambridge CB2 2QQ [L. H-D.]; United Kingdom

Members of the transforming growth factor ß (TGF-ß) family are potent inhibitors of the growth of many epithelial cell types. Trans-membrane signaling by TGF-ß occurs via a complex of the serine/threonine kinases TGF-ß type 1 receptor and TGF-ß type 2 receptor (TGFBR2), and inactivating mutations in the latter have recently been detected in some primary tumors and in several types of tumor-derived cell lines. The most common mutations that have been identified in TGFBR2 are frameshifts in a repetitive polyadenine region in replication error-positive colorectal carcinomas that result in a truncated protein and absence of receptor expression at the cell surface. A number of point mutations in the highly conserved serine/threonine kinase domain of TGFBR2 have also been reported, some of which have been correlated with either loss of trans-phosphorylation of TGF-ß type 1 receptor or constitutive activation of trans-phosphorylation. No TGFBR2 mutations have been reported in human breast tumors, but anomalous expression of TGF-ß in breast carcinomas suggests that TGF-ß signaling may be defective. We have therefore systematically examined unmatched sets of 17 primary and 17 recurrent breast tumor samples for mutations in TGFBR2, restricted to those regions of the gene in which mutations have previously been reported. None of the previously reported mutations was detected, but four novel mutations (V387M, N435S, V447A, and L452M) were found in the kinase domain in recurrent tumors. No mutations were detected in primary tumors. TGF-ß signaling was significantly inhibited by each of the N435S, V447A, and L452M mutations.

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